Method of producing 1-alkyl-3-aryl-5-difluoromethoxy-1H-pyrazoles

ABSTRACT

The invention relates to a method of preparing 1-alkyl-3-aryl-5-difluoromethoxy-1H-pyrazoles of the formula (I), wherein aryl represents a mono- or polysubstituted phenyl ring, and R 1  represents C 1 -C 4  alkyl. The inventive method is characterized by reacting, in a first reaction step, a β-ketoester of the general formula (II) with hydrazine and by successively reacting the reaction product obtained with chlorodifluoromethane and a compound R 1 -L, wherein R 1  has the meanings indicated above and L represents the leaving group of a nucleophilic displacement reaction.

The present invention relates to a process for preparing1-alkyl-3-aryl-5-difluoromethoxy-1H-pyrazoles of the formula I

in which Aryl is a mono- or polysubstituted phenyl ring and R¹ isC₁-C₄-alkyl.

1-Alkyl-3-aryl-5-difluoromethoxy-1H-pyrazoles of the formula I areimportant herbicides. In the prior art, they have hitherto been preparedin a synthesis which comprises the following steps:

-   1. reaction of 3-aryl-3-oxopropionic esters II (hereinbelow also    referred to as β-keto esters II)    -   in which R^(a) is, for example, C₁-C₄-alkyl, and aryl has the        meanings given above, with alkylhydrazines and-   2. reaction of the resulting 3-aryl-5-hydroxy-1H-pyrazole    substituted by alkyl on the pyrazole nitrogen with a    halodifluoromethane.

These processes are described, for example, in EP-A 443059, EP-A 361114,JP 03072460, JP 04225937 and JP 06199804.

This procedure has two grave disadvantages. Firstly, for step 1, highlyexpensive alkylhydrazines have to be used. Secondly, in the reaction ofII with alkylhydrazine, in addition to the desired1-alkyl-3-aryl-5-hydroxy-1H-pyrazoles IV, considerable amounts of theisomers V are formed.

In general, the ratio of desired product IV to the undesired isomer V isonly 3:1 or less. Moreover, the cyclization yields in step 1, based onthe expensive alkylhydrazine employed, are low. Furthermore, owing totheir similar physical properties, the separation of the hydroxypyrazoleisomers IV and V is very complicated. The separation of the reactionproducts of the isomer mixture IV+V with halodifluoromethane (step 2) islikewise unfavorable, since V, in contrast to IV, has a strong tendencyto form N-difluoromethylpyrazolones which give rise to further problemsduring the work-up of the target product I.

It is an object of the present invention to provide a process forpreparing the 1-alkyl-3-aryl-5-difluoromethoxy-1H-pyrazoles I defined atthe outset, which process avoids the use of alkylhydrazine and whichaffords the compound I in good, but at least comparable, total yields.

Surprisingly, it has been found that the 3-aryl-5-hydroxy-1H-pyrazolesIII or their tautomers, the 3-arylpyrazol-5-ones of the formula IIIa,

which can be obtained in good yields by reacting 3-aryl-3-ketopropionicesters II with hydrazine, can be converted with high selectivity byreaction with alkylating agents into the1-alkyl-3-aryl-5-hydroxy-1H-pyrazoles IV, and that it is furthermorepossible, by reacting the compounds III or IIIa withchlorodifluoromethane, to prepare, with good selectivities, thedifluoromethoxypyrazoles of the formula VI

which for their part can be converted selectively and with good yieldsby reaction with alkylating agents into the1-alkyl-3-aryl-5-difluoromethoxy-1H-pyrazoles I.

Accordingly, the invention relates to a process for preparing1-alkyl-3-aryl-5-difluoromethoxy-1H-pyrazoles of the formula I definedat the outset, which process comprises reacting, in a first reactionstep, a β-keto ester of the formula II with hydrazine, giving ahydroxypyrazole of the formula III, which is subsequently, in a secondand third reaction step, reacted successively with chlorodifluoromethaneand a compound R¹-L, where R¹ has the meanings given above and L is anucleophilically displaceable leaving group. Here, it is possible toinitially react the hydroxypyrazole III obtained in step 1 with acompound R¹-L and then react the resulting 1-alkylated hydroxypyrazoleIV, if appropriate as a mixture with its isomer V, withchlorodifluoromethane (hereinbelow referred to as variant A). It is alsopossible to initially react III with chlorodifluoromethane and, toprepare the compound I, to react the resulting difluoromethoxypyrazoleVI with a compound R¹-L (hereinbelow referred to as variant B).

Nucleophilically displaceable leaving groups L are, in principle,understood as meaning all groups which are known to be displaceableunder the conditions of an alkylation of amines by the nucleophilicN-atom. These include, in particular, the halogen atoms chlorine,bromine and iodine, alkyl- and arylsulfonate groups, for examplephenylsulfonate, tolylsulfonate (tosylate) and mesylate, carboxylategroups, such as acetate, furthermore alkyl sulfate groups, such asmethyl sulfate and ethyl sulfate, and also dialkyloxonium groups, suchas the dimethyloxonium group or diethyloxonium group in Meerwein salts.Preferred groups L are iodine, bromine, chlorine and the groups OSO₂—OR¹and [O(R¹)₂]⊕. Particular preference is given to the group OSO₂—OR¹, inparticular if R¹ is a methyl group.

Examples of other meanings are:

-   C₁-C₄-alkyl: for example methyl, ethyl, propyl, 1-methylethyl,    butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl;-   C₁-C₆-alkyl: C₁-C₄-alkyl as mentioned above, and also, for example,    n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,    2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl,    1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,    4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,    1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,    3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,    1,1,2-trimethylpropyl, 1-ethyl-1-methylpropyl or    1-ethyl-3-methylpropyl;-   C₁-C₄-alkoxy and the alkoxy moieties of C₁-C₄-alkoxy-C₁-C₄-alkyl and    C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl: for example methoxy, ethoxy,    propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or    1,1-dimethylethoxy;-   C₁-C₄-alkoxy-C₁-C₄-alkyl: C₁-C₄-alkyl which is substituted by    C₁-C₄-alkoxy as mentioned above, i.e., for example, methoxymethyl,    ethoxymethyl, propoxymethyl, (1-methylethoxy)methyl, butoxymethyl,    (1-methylpropoxy)methyl, (2-methylpropoxy)methyl,    (1,1-dimethylethoxy)methyl, 2-(methoxy)ethyl, 2-(ethoxy)ethyl,    2-(propoxy)ethyl, 2-(1-methylethoxy)ethyl, 2-(butoxy)ethyl,    2-(1-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl,    2-(1,1-dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl,    2-(propoxy)propyl, 2-(1-methylethoxy)propyl, 2-(butoxy)propyl,    2-(1-methylpropoxy)propyl, 2-(2-methylpropoxy)propyl,    2-(1,1-dimethylethoxy)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl,    2-(propoxy)butyl, 2-(1-methylethoxy)butyl, 2-(butoxy)butyl,    2-(1-methylpropoxy)butyl, 2-(2-methylpropoxy)butyl,    2-(1,1-dimethylethoxy)butyl;-   C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl: C₁-C₄-alkyl which is substituted    by C₁-C₄-alkoxycarbonyl, i.e., for example, methoxycarbonylmethyl,    ethoxycarbonylmethyl, propoxycarbonylmethyl,    (1-methylethoxy)carbonylmethyl, butoxycarbonylymethyl,    (1-methylpropoxy)carbonylmethyl, (2-methylpropoxy)carbonylmethyl,    (1,1-dimethylethoxy)carbonylmethyl, 2-(methoxycarbonyl)ethyl,    2-(ethoxycarbonyl)ethyl, 2-(propoxycarbonyl)ethyl,    2-(1-methylethoxycarbonyl)ethyl, 2-(butoxycarbonyl)ethyl,    2-(1-methylpropoxycarbonyl)ethyl, 2-(2-methylpropoxycarbonyl)ethyl,    2-(1,1-dimethylethoxycarbonyl)ethyl, 2-(methoxycarbonyl)propyl,    2-(ethoxycarbonyl)propyl, 2-(propoxycarbonyl)propyl,    2-(1-methylethoxycarbonyl)propyl, 2-(butoxycarbonyl)propyl,    2-(1-methylpropoxycarbonyl)propyl,    2-(2-methylpropoxycarbonyl)propyl,    2-(1,1-dimethylethoxycarbonyl)propyl, 2-(methoxycarbonyl)butyl,    2-(ethoxycarbonyl)butyl, 2-(propoxycarbonyl)butyl,    2-(1-methylethoxycarbonyl)butyl, 2-(butoxycarbonyl)butyl,    2-(1-methylpropoxycarbonyl)butyl, 2-(2-methylpropoxycarbonyl)butyl,    2-(1,1-dimethylethoxycarbonyl)butyl;-   C₁-C₆-alkylcarbonyl: for example acetyl, propionyl, n-butyryl,    isobutyryl, pivaloyl, n-hexenoyl;-   C₂-C₆-alkenyl: for example ethenyl, prop-1-en-3-yl, but-1-en-4-yl,    1-methylprop-2-en-1-yl, 2-methylprop-2-en-1-yl, 2-buten-1-yl,    1-penten-3-yl, 1-penten-4-yl, 2-penten-4-yl, 1-methylbut-2-en-1-yl,    2-methylbut-2-en-1-yl, 3-methylbut-2-en-1-yl, 1-methylbut-3-en-1-yl,    2-methylbut-3-en-1-yl, 3-methylbut-3-en-1-yl,    1,1-dimethylprop-2-en-1-yl, 1,2-dimethylprop-2-en-1-yl,    1-ethylprop-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl,    1-methylpent-3-en-1-yl, 2-methylpent-3-en-1-yl,    3-methylpent-3-en-1-yl, 4-methylpent-3-en-1-yl,    1-methylpent-4-en-1-yl, 2-methylpent-4-en-1-yl,    3-methylpent-4-en-1-yl, 4-methylpent-4-en-1-yl,    1,1-dimethylbut-2-en-1-yl, 1,1-dimethylbut-3-en-1-yl,    1,2-dimethylbut-2-en-1-yl, 1,2-dimethylbut-3-en-1-yl,    1,3-dimethylbut-2-en-1-yl, 1,3-dimethylbut-3-en-1-yl,    2,2-dimethylbut-3-en-1-yl, 2,3-dimethylbut-2-en-1-yl,    2,3-dimethylbut-3-en-1-yl, 3,3-dimethylbut-2-en-1-yl,    1-ethylbut-2-en-1-yl, 1-ethylbut-3-en-1-yl, 2-ethylbut-2-en-1-yl,    2-ethylbut-3-en-1-yl, 1,1,2-trimethylprop-2-en-1-yl,    1-ethyl-1-methylprop-2-en-1-yl or 1-ethyl-2-methylprop-2-en-1-yl;-   C₂-C₆-alkynyl: for example ethynyl, propargyl, but-1-yn-3-yl,    but-1-yn-4-yl, but-2-yn-1-yl, pent-1-yn-3-yl, pent-1-yn-4-yl,    pent-1-yn-5-yl, pent-2-yn-1-yl, pent-2-yn-4-yl, pent-2-yn-5-yl,    3-methylbut-1-yn-3-yl, 3-methylbut-1-yn-4-yl, hex-1-yn-3-yl,    hex-1-yn-4-yl, hex-1-yn-5-yl, hex-1-yn-6-yl, hex-2-yn-1-yl,    hex-2-yn-4-yl, hex-2-yn-5-yl, hex-2-yn-6-yl, hex-3-yn-1-yl,    hex-3-yn-2-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl,    3-methylpent-1-yn-5-yl, 4-methylpent-2-yn-4-yl or    4-methylpent-2-yn-5-yl.

Suitable substituents for aryl are, in principle, all atoms or atomgroups which are inert under the reaction conditions and which are inparticular unreactive with respect to alkylating agents R¹-L andhalodifluoromethanes. Here, it is also possible for 2 substituentsattached to adjacent carbon atoms to form a 3-, 4- or 5-memberedsaturated or unsaturated chain. The chain may also comprise, as chainmembers, one or two heteroatoms, for example nitrogen, sulfur or oxygen,and/or one or two carbonyl or thiocarbonyl functions. Examples ofsuitable substituents are halogen, C₁-C₄-alkyl, which may additionallybe substituted by halogen, phenyl, a C₁-C₄-alkoxy group, aC₁-C₄-alkoxycarbonyl group or a C₁-C₄-alkylcarbonyloxy group,C₂-C₆-alkenyl, C₂-C₆-alkynyl, NO₂, COOR⁵, OR⁶, C(O)R⁷, SO_(n)R⁸ andSO_(n)NR⁹R¹⁰, where R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ independently of oneanother are selected from the group consisting of hydrogen, C₁-C₄-alkyl,C₃-C₄-alkenyl, C₃-C₄-alkynyl, C₁-C₄-alkoxy-C₁-C₄-alkyl andC₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl and where n is 0, 1 or 2, furthermoreNH(CO—R¹²) and N(CO—R¹²)₂, where R¹² has one of the meanings mentionedfor R⁶ and is in particular C₁-C₄-alkyl. Examples of chains are1,3-propylene, 1,4-butylene, 1,3-dioxypropylene, 1-oxy-1,4-butylene andthe like.

All reactions described here are carried out in reaction vessels whichare customary for such reactions, it being possible to carry out thereaction either continuously or batchwise. In general, the reaction inquestion is carried out under atmospheric pressure. In the case oflow-boiling solvents, it is also possible to carry out the reaction inquestion under superatmospheric pressure.

The preparation of the 3-aryl-5-hydroxypyrazoles III in step 1 of theprocess according to the invention is carried out similarly to thepreparation of N-substituted pyrazolones or hydroxypyrazolones startingfrom β-keto esters of the formula II, where, in contrast to the priorart, the β-keto ester II is not reacted with an alkylhydrazine but withhydrazine, either in pure form or as hydrazine hydrate.

Preference is given to using hydrazine, or an equivalent amount ofhydrazine hydrate, in at least equimolar amount or in excess, where arelatively large excess, for example more than 20 mol %, based on 1 molof β-keto ester II, is generally not required. Preference is given tousing 1.01 to 1.1 mol, in particular about 1.05 mol, of hydrazine permole of compound II.

The reaction of II with hydrazine is preferably carried out in anorganic solvent. Examples of suitable organic solvents are protic polarsolvents, for example aliphatic alcohols having preferably 1 to 4 carbonatoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol or tert-butanol, aromatic hydrocarbons, such as benzene,toluene, xylenes, cumene, chlorobenzene, nitrobenzene ortert-butylbenzene, aprotic polar solvents, for example cyclic or acyclicethers, such as diethyl ether, tert-butylmethyl ether (MTBE),tetrahydrofuran (THF) or dioxane, cyclic or acyclic amides, such asdimethylformamide, dimethylacetamide, N-methylpyrrolidone ortetramethylurea, and also mixtures of the solvents mentioned above. Thereaction is preferably carried out in a protic polar solvent, inparticular in a C₁-C₄-alkanol and particularly preferably in ethanol.

The reaction is preferably carried out at temperatures above 0° C., inparticular at at least 10° C. and particularly preferably at at least15° C. In general, the upper temperature limit is the boiling point ofthe solvent in question if the reaction is carried out under atmosphericpressure. Preferably, a reaction temperature of 100° C., in particular60° C. and particularly preferably 40° C. is not exceeded. For practicalreasons, the reaction is frequently carried out at room temperature.

Depending on the reactivity of the ester II and the reactiontemperature, the reaction time required for complete conversion is inthe range from 1 h to 48 h and preferably in the range from 10 to 15 h.

Work-up of the reaction mixture and isolation of the hydroxypyrazole III(or its tautomer IIIa) are carried out in a customary manner by removingthe solvent, for example by extraction, distillation or filtration.Further purification can take place, for example, by crystallization orchromatographically. However, the product is frequently obtained in apurity which does not require further purification steps. This is truein particular when protic polar solvents are used. In these solvents,the hydroxypyrazoles III are generally poorly soluble, if at all, andthey crystallize from the reaction solution in a form which issufficiently pure to allow isolation by filtration. Step 1 of theprocess according to the invention affords the hydroxypyrazoles III ingood to very good yields of generally at least 60%.

In the process according to the invention, the preparation of thehydroxypyrazole III is followed by an alkylation step to introduce thesubstituent R¹ and the introduction of the difluoromethyl group.

The reaction of the hydroxypyrazole III in variant A or thedifluoromethoxypyrazole VI in variant B with the alkylating agent R¹-Lis preferably carried out in an aprotic organic solvent, for example oneof the aromatic hydrocarbons mentioned in step 1, a cyclic or acyclicether or a cyclic or acyclic amide, or mixtures of these solvents.Preference is given to aromatic hydrocarbons and in particularalkylaromatic compounds such as xylene and toluene.

The alkylating agents R¹-L are preferably selected from the groupconsisting of C₁-C₄-alkyl chlorides, C₁-C₄-alkyl bromides, C₁-C₄-alkyliodides and, in particular, di-C₁-C₄-alkyl sulfates, and particularpreference is given to the respective primary alkyl compounds and inparticular the methyl compounds. A very particularly preferredalkylating agent R¹-L is dimethyl sulfate.

In general, the alkylating agent R¹-L is employed in an at leastequimolar amount, preferably not more than 2 mol, in particular not morethan 1.6 mol, per mole of the pyrazole III or VI in question. Withparticular preference, the alkylating agent R¹-L is, in variant A,employed in an amount of from 1.4 to 1.6 mol per mole of the compoundIII and, in variant B, in an amount of from 1.0 to 1.3 mol per mole ofcompound VI.

The reaction of the pyrazoles III or VI with R¹-L can be carried out inthe absence or presence of an auxiliary base. The reaction of III withR¹-L is preferably carried out in the presence of an auxiliary base, andthe reaction of VI with R¹-L is preferably carried out in the absence ofan auxiliary base.

Suitable auxiliary bases are alkali metal and alkaline earth metalhydroxides, for example sodium hydroxide, potassium hydroxide or calciumhydroxide, and also, preferably, alkali metal and alkaline earth metalcarbonates, in particular sodium carbonate or potassium carbonate. Theauxiliary base is preferably employed in a substoichiometric amount(calculated as base equivalents), preferably in an amount of from 0.3 to0.5 equivalents, based on the pyrazole III or VI in question.

The reaction of III or VI with R¹-L is generally carried out attemperatures of at least 0° C. up to the boiling point of the solvent inquestion, preferably in the range from 20° C. to 120° C. and inparticular in the range from 70° C. to 120° C.

The required reaction time is generally in the range from 0.5 h to 12 hand preferably in the range from 1 to 6 h.

In general, following the reaction, ammonia, an ammonium salt such asammonium chloride or ammonium sulfate or an aliphatic or cycloaliphaticamine is added to the reaction mixture to destroy excess alkylatingagent R¹-L. It is also possible to treat the reaction mixture with analkali metal hydroxide, preferably in the form of an aqueous solution.Frequently, the alkylating agent is destroyed using aqueous ammoniasolution or a primary or secondary aliphatic or cycloaliphatic amine,for example diethylamine. In the case of relatively volatile compoundssuch as alkyl chlorides, bromides and iodides, it may not be necessaryto destroy the alkylating agent.

Work-up of the reaction mixture and isolation of the N-alkylatedpyrazoles IV or I is carried out in a customary manner by removing thesolvent, for example by extraction, distillation or filtration. Furtherpurification can be carried out, for example, by crystallization orchromatographically.

Surprisingly, the alkylation of III in variant A takes place withconsiderably higher selectivity for the formation of IV as compared toits isomer V, for example 4:1 and better, compared to the reaction of IIwith alkylhydrazines, so that it is possible to isolate the compound IVin a relatively uncomplicated manner from the crude product. IV, forexample, can be isolated by acidifying the reaction mixture, preferablyto a pH of <2, for example pH=1. As a result, the compound IVprecipitates as a solid from the reaction solution. This solid can thenbe purified, for example by crystallization from an organic solvent,preferably from a polar organic solvent which is at least partiallymiscible with water, such as methanol, ethanol, ethers, for example THF,MTBE or dioxane, and amides, for example DMF, DMAA or NMP, particularpreference being given to mixtures of these solvents with water,especially to aqueous ethanol. Moreover, the yields of IV, based on II,obtainable by variant A according to the invention are considerablyhigher than in the reaction of II with alkylhydrazines. Furthermore, theuse of expensive alkylhydrazine is avoided.

The alkylation of VI according to variant B, in turn, affords thecompound I in particularly good yields and with high selectivity, withthe formation of only negligible amounts of the undesired isomer5-aryl-1-alkyl-3-difluoromethoxypyrazole of the formula.

In principle, the reaction of III or IV with chlorodifluoromethane hasalready been disclosed in the publications mentioned at the outset. Inthis respect, these publications are incorporated herein by way ofreference.

The reaction of III or IV is generally carried out by adding, forexample as a gas, an at least equivalent amount of chlorodifluoromethaneto the reaction mixture. Preferably, an excess of chlorodifluoromethaneis used. In general, it is not required to use an excess of more than 10mol per mole of III or IV. Preference is given to using from 3 to 7 molof chlorodifluoromethane. In variant A, an excess of 8 mol, inparticular 6 mol, of chlorodifluoromethane per mole of pyrazole IV ispreferably not exceeded.

In principle, it has been found to be advantageous to carry out thereaction of III or IV with chlorodifluoromethane in the presence of abase. Suitable auxiliary bases are organic, preferably aliphatic orcycloaliphatic, amines, such as diethylamine, triethylamine,cyclohexylamine and the like, alkali metal and alkaline earth metalhydroxides, for example sodium hydroxide, potassium hydroxide or calciumhydroxide, alkali metal and alkaline earth metal carbonates, such assodium carbonate or potassium carbonate, and also alkali metalalkoxides, such as sodium methoxide or potassium methoxide or sodiumethoxide or potassium ethoxide. Particularly preferred bases are alkalimetal hydroxides, in particular sodium hydroxide and potassiumhydroxide. The auxiliary base is preferably employed in an at leastequimolar amount (calculated as base equivalents), preferably in excess,for example in an amount of from 1.5 to 2.0 mol, based on the pyrazoleIII or IV in question. The difluoromethylation of III (variant B) ispreferably carried out at a controlled pH of at least 8, for example inthe range from pH 8 to pH 12-13.

In general, reactions with chlorodifluoromethane are carried out in anorganic solvent, preference being given to polar organic solvents whichare preferably at least partially water-miscible, such as ethers, forexample, THF, MTBE or dioxane, and amides, for example DMF, DMAA or NMP,and mixtures of these solvents with water. Particular preference isgiven to mixtures of at least 70% by volume and up to 99% by volume, inparticular 85-95% by volume, of cyclic ether and 5-15% by volume ofwater, and to the abovementioned amides.

The reaction is preferably carried out at temperatures above 40° C., inparticular at least 60° C. and particularly preferably in the range from70° C. to 90° C.

Work-up of the reaction mixture and isolation of the difluoromethylatedpyrazoles I or VI is carried out in a customary manner by removing thesolvent, for example by extraction, distillation or filtration. Furtherpurification can be carried out, for example, by crystallization orchromatographically.

The process according to the invention is particularly suitable forpreparing compounds where R¹=methyl.

Aryl is preferably phenyl which has one, two, three or four, preferably2 or 3, of the abovementioned substituents, where 2 substituentsattached to adjacent carbon atoms may also form a 3-, 4- or 5-memberedsaturated or unsaturated chain. The chain may also include one or twoheteroatoms, for example nitrogen, sulfur or oxygen, and/or one or twocarbonyl or thiocarbonyl functions, as chain members.

Preferred substituents are halogen, C₁-C₄-alkyl, which may beunsubstituted or substituted by halogen, phenyl or a C₁-C₄-alkoxy group,alkenyl, alkynyl, NO₂, a group COOR⁵ or a group OR⁶, where R⁵ and R⁶independently of one another are selected from the group consisting ofhydrogen, C₁-C₄-alkyl, C₃-C₄-alkenyl, C₃-C₄-alkynyl,C₁-C₄-alkoxy-C₁-C₄-alkyl and C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl. Theprocess is particularly suitable for preparing compounds I in which arylis a group of the formula

in which R² and R³ independently of one another are hydrogen or one ofthe abovementioned substituents and, in particular, have the followingmeanings:

-   R² is hydrogen, in particular fluorine or chlorine,-   R³ is hydrogen, C₁-C₄-alkyl, NO₂, COOR⁵ or OR⁶, where R⁵ and R⁶    independently of one another are hydrogen, C₁-C₄-alkyl,    C₃-C₄-alkenyl, C₃-C₄-alkynyl, C₁-C₄-alkoxy-C₁-C₄-alkyl or    C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl.

R³ is preferably hydrogen or a group OR⁶. R⁶ is preferably C₁-C₄-alkyl,C₃-C₄-alkynyl, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl. R³ is in particularhydrogen.

The compounds of the formula VIa

obtained as intermediates in variant B of the process according to theinvention, in which R² and R³ have the meanings given above, are noveland also form part of the subject matter of the present invention.

The examples below serve to illustrate the invention; they are not to beunderstood as imposing any limitations, however.

The starting material used in the examples below was methyl3-(2,4-dichlorophenyl)-3-oxopropionate or ethyl3-(4-chloro-2-fluorophenyl)-3-oxopropionate, obtainable by basiccondensation of the corresponding 2,4-dihaloacetophenones with dimethylcarbonate and diethyl carbonate, respectively.

EXAMPLE 13-(4-Chloro-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole(Variant B)

1.1 3-(4-Chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole

428.4 g of ethyl 3-(4-chloro-2-fluorophenyl)-3-oxopropionate wereinitially charged in 1400 ml of ethanol. Over a period of 15 min, 92 gof hydrazine hydrate were added dropwise, the mixture was stirred atroom temperature overnight, the precipitated solid was filtered off andthe filtrate was concentrated to ⅓ of its original volume. The mixturewas stirred for another two nights, the resulting solid was filtered offwith suction and the filtrate was again concentrated to ⅓ of itsoriginal volume. This gave a total of 289.1 g (77.7%) of3-(4-chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole as a colorless solid.M.p.: 194° C.

¹H-NMR (DMSO-d6, TMS): δ 5.88 (s, 1H), 7.35 (dd, 1H), 7.52 (dd, 1H),7.83 (t, 1H), 9.0-11.2 (br), 11.2-13.0 (br).

1.2 3-(4-Chloro-2-fluorophenyl)-5-difluoromethoxy-1H-pyrazole

64 g of the 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole obtainedin step 1.1 were initially charged in 600 ml of dioxane. A solution of24 g of sodium hydroxide in 70 ml of water was added, and the mixturewas heated at reflux. With stirring, 238.7 g (2.76 mol, 9.2 eq.) ofgaseous chlorodifluoromethane were added, and during the addition the pHwas monitored constantly and, when it approached the neutral range(pH<9), increased by addition of additional NaOH solution to about pH12. After 6 h, the mixture was allowed to cool, 1800 ml of water wereadded and the mixture was extracted twice with in each case 500 ml ofMTBE. The combined organic phases were washed with in each case 500 mlof water and saturated sodium chloride solution, dried over Na₂SO₄,filtered and concentrated. This gave 58.7 g of crude3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1H-pyrazole. 32.3 g ofthis mixture were distilled under reduced pressure, giving 11.6 g of thetitle compound as an oil of a purity of 86%. Yield: 22.9%

1H-NMR (DMSO-d6, TMS): δ 6.32 (d, 1H), 7.14 (t, 1H), 7.32 (dd, 2H), 7.39(dd, 1H), 7.81 (t, 1H), 12.9 (s, 1H)

1.3 3-(4-Chloro-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole

11.6 g of the 3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1H-pyrazole(purity 86%) obtained in step 1.2 were initially charged in 100 ml oftoluene. 6.2 g of dimethyl sulfate were added dropwise, and the mixturewas heated at reflux for 3 h. After cooling, 25 ml of saturated aqueousNH₄Cl solution were added, the mixture was stirred for 1 h and theorganic phase was separated off and washed with water until neutral.Drying over Na₂SO₄ and concentration gave 11.3 g of3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole as anoil of a purity of 82.4% (GC). Yield: 88.6%

¹H-NMR (DMSO-d6, TMS): δ 3.41 (s, 1H), 3.78 (s, 3H), 6.42 (d, 1H), 7.36(dd, 1H), 7.38 (t, 1H), 7.44 (dd, 1H) 7.92 (t, 1H)

EXAMPLE 23-(4-Chloro-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole(Variant A):

2.1 3-(4-Chloro-2-fluorophenyl)-5-hydroxy-1-methyl-1H-pyrazole

50 g of 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1H-pyrazole from Example1.1 were initially charged in 1500 ml of toluene. 35.5 g of dimethylsulfate were then added, and the mixture was heated at reflux for 3 h.After cooling to room temperature, the mixture was made alkaline usingammonia, stirred overnight and acidified by addition of hydrochloricacid. The mixture was then cooled to 0° C., and the precipitated solidwas filtered off. After drying, 49.4 g of3-(4-chloro-2-fluorophenyl)-5-hydroxy-1-methyl-1H-pyrazole were obtainedas crude product (purity according to NMR about 80%, impurityessentially starting material), which was purified by recrystallizationfrom toluene to >95% purity. Yield 49.4 g, 74.1%. M.p.: 204° C.

¹H-NMR (DMSO-d6, TMS): δ 3.65 (s, 3H), 5.92 (d, 1H), 7.35 (d, 1H), 7.52(d, 2H), 7.94 (t, 1H)

2.2 3-(4-Chloro-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole

57.1 g of 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1-methyl-1H-pyrazolefrom Example 2.1 were initially charged in 500 ml of dioxane. A solutionof 18.8 g of NaOH in 50 ml of H₂O was added, the mixture was heated atreflux and 85 g (0.98 mol=3.9 eq.) of gaseous chlorodifluoromethane wereintroduced. The mixture was poured into 1.5 l of water and extractedtwice with 500 ml of MTBE, and the combined organic phases wereextracted once with 500 ml of water and once with 500 ml of saturatedsodium chloride solution. Drying and concentration of the organic phasegave 57.6 g of 53% pure3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole as anoil which was purified further by vacuum distillation. This gave thetitle compound in a purity of 94% in a yield of 43.8%.

COMPARATIVE EXAMPLE 1 Preparation of3-(4-chloro-2-fluorophenyl)-5-hydroxy-1-methyl-1H-pyrazole usingmethylhydrazine

1000 g of ethyl 3-(4-chloro-2-fluorophenyl)-3-oxopropionate wereinitially charged in 2500 ml of diethylene glycol dimethyl ether, and650 g of methylhydrazine (35% in H₂O) were added dropwise. The reactionmixture was heated at reflux for 2 h, allowed to cooled and poured intoa mixture of 5 l of water and 300 ml of ethyl acetate. Further portionsof ethyl acetate were added to the resulting slimy precipitate until acrystalline material was formed which was then filtered off. The productobtained after drying under reduced pressure contained the titlecompound in a mixture with the isomeric5-(4-chloro-2-fluorophenyl)-3-hydroxy-1-methyl-1H-pyrazole in a molarratio of 2.5:1. Crystallization from ethyl acetate/ethanol (7:3 v/v)gave 209 g of the title compound in a purity of about 98% (yield 22.5%).

EXAMPLE 3 3-(2,4-Dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole(Variant B)

3.1 3-(2,4-Dichlorophenyl)-5-hydroxy-1H-pyrazole

970 g of methyl 3-(2,4-dichlorophenyl)-3-oxopropionate were initiallycharged in 4000 ml of ethanol. Over a period of 15 min, 201 g ofhydrazine hydrate were added dropwise, the mixture was stirred at roomtemperature overnight, the precipitated solid was filtered off and thefiltrate was concentrated to ⅓ of its original volume. The filtrate wasstirred for another two nights, the resulting solid was filtered offwith suction and the filtrate was again concentrated to ⅓ of itsoriginal volume. This gave a total of 714.2 g (79.4%) of3-(2,4-dichlorophenyl)-5-hydroxy-1H-pyrazole as a colorless solid. M.p.:198° C.

¹H-NMR (DMSO-d6, TMS): δ 5.92 (s, 1H), 7.50 (d, 1H), 7.6-7.8 (m, 2H),11.6-12.6 (br)

3.2 3-(2,4-Dichlorophenyl)-5-difluoromethoxy-1H-pyrazole

237 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1H-pyrazol from Example 3.1were initially charged in 2160 ml of dioxane. A solution of 84 g ofsodium hydroxide in 250 ml of water was added, and the mixture washeated at reflux. With stirring, 620 g (7.17 mol, 6.9 eq.) of gaseouschlorodifluoromethane were introduced, and, during the addition, the pHwas monitored continuously and when it approached the neutral range (pH9) increased to pH 12 by addition of additional NaOH solution. After 6h, the mixture was allowed to cool, 1.7 l of water were added and themixture was extracted three times with in each case 500 ml of MTBE. Thecombined organic phases were washed with in each case 1500 ml of waterand saturated sodium chloride solution, dried over Na₂SO₄, filtered andconcentrated. The residue was suspended in 500 ml of cyclohexane andheated to reflux, and undissolved particles were filtered off. Theresidue was once more extracted with 200 ml of boiling cyclohexane. Thecombined filtrates were concentrated to obtain the title compound. Thisgave 136.7 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1H-pyrazole asa solid. (Yield 47.3%).

¹H-NMR (DMSO-d6, TMS): δ 6.42 (s, 1H), 7.35 (t, 1H), 7.57 (dd, 1H), 7.63(d, 1H), 7.78 (d, 2H), 13.8-14.2 (br)

3.3 3-(2,4-Dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole

457.2 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1H-pyrazole fromExample 3.2 were initially charged in 2300 ml of toluene. 227.3 g ofdimethyl sulfate were added dropwise, and the mixture was heated atreflux for 3 h. After cooling, 500 ml of saturated aqueous NH₄Clsolution were added, the mixture was stirred for 1 h and the organicphase was separated off and washed with water until neutral. Drying overNa₂SO₄ and concentration gave 377.8 g of3-(2,4-dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole of apurity of 92.9% (GC). Yield: 73.1%. M.p.: 35° C.

¹H-NMR (CDCl₃, TMS): δ 3.78 (s, 3H), 6.41 (s, 1H), 6.58 (t, 1H), 7.26(dd, 1H), 7.42 (d, 1H), 7.72 (d, 1H)

EXAMPLE 4 3-(2,4-Dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole(Variant A)

4.1 3-(2,4-Dichlorophenyl)-5-hydroxy-1-methyl-1H-pyrazole

30 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1H-pyrazole from Example 3.1were initially charged in 750 ml of toluene. 23.1 g of dimethyl sulfateand 7.5 g of potassium carbonate were added, and the mixture was heatedat reflux for 2 h. After cooling to room temperature, the mixture wasmade alkaline using ammonia and stirred overnight. The mixture wasacidified by addition of hydrochloric acid (pH about 1) and cooled toroom temperature, and the precipitated solid was filtered off. Dryinggave 21.4 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1-methyl-1H-pyrazole(purity according to GC 99.2%, yield 66.8%). M.p.: 128° C.

¹H-NMR (DMSO-d6, TMS): δ 3.59 (s, 3H), 5.92 (s, 1H), 7.42 (dd, 1H), 7.61(d, 1H), 7.80 (d, 1H), 11.2 (s, 1H)

4.2 3-(2,4-Dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole

9 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1-methyl-1H-pyrazole fromExample 4.1 were initially charged in 50 ml of dimethylacetamide, and5.4 g of potassium carbonate were added. The mixture was heated at 90°C., and 48 g of gaseous chlorodifluoromethane were introduced over aperiod of 1 h. The mixture was poured into 800 ml of water and extractedtwice with 300 ml of MTBE, and the combined organic phases wereextracted once with 100 ml of water and once with 100 ml of saturatedsodium chloride solution. Drying and concentration of the organic phasegave 10.2 g of3-(2,4-dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole of apurity of 56% (yield 50.2%, based on the title compound), which waspurified further by vacuum distillation.

COMPARATIVE EXAMPLE 2 Preparation of3-(2,4-dichlorophenyl)-5-hydroxy-1-methyl-1H-pyrazole usingmethylhydrazine

1980 g of methyl 3-(2,4-dichlorophenyl)-3-oxopropionate were initiallycharged in 3000 ml of diethylene glycol dimethyl ether. Over a period of30 min, 728 g of methylhydrazine (51% in H₂O) were added dropwise, andthe mixture was heated at reflux for 2.5 h. After cooling, the reactionmixture was poured into a mixture of 6 l of water and 600 ml of ethylacetate, and the precipitated solid was filtered off with suction. Thesolid was recrystallized from ethyl acetate/ethanol (7:3 v/v) and driedunder reduced pressure. This gave 894 g of an about 80% pure mixture of3-(2,4-dichlorophenyl)-5-hydroxy-1-methyl-1H-pyrazole and5-(2,4-dichlorophenyl)-3-hydroxy-1-methyl-1H-pyrazole in a molar ratioof 3:1. Repeated fractional recrystallization from ethyl acetate/ethanol(7:5 v/v) gave 444.5 g of the pure title compound (purity>98%). Yield24.1%.

1. A process for preparing 1-alkyl-3-aryl-5-difluoro-methoxy-1H-pyrazoles of the formula I

in which Aryl is a mono- or polysubstituted phenyl ring and R¹ isC₁-C₄-alkyl, which comprises reacting, in a first reaction step, aβ-keto ester of the formula II,

in which R^(a) is C₁-C₄-alkyl and Aryl has the meanings given above withhydrazine, giving a hydroxypyrazole of the formula III

which is reacted successively with chlorodifluoromethane and analkylating agent R¹-L in which R¹ has the meanings given above and L isa nucleophilically displaceable leaving group.
 2. A process as claimedin claim 1, wherein the hydroxypyrazole III is initially reacted with acompound R¹-L and the resulting 1-alkyl-3-aryl-5-hydroxypyrazole IV

is reacted with chlorodifluoromethane.
 3. A process as claimed in claim1 or 2, wherein the reaction of the hydroxypyrazoles III or IV withchlorodifluoromethane is carried out in the presence of a base.
 4. Aprocess as claimed in claim 3, wherein the base is selected from thegroup consisting of alkali metal hydroxides and alkali metal carbonates.5. A process as claimed in claim 1, wherein aryl is as defined below:

in which R² and R³ have the following meanings: R² is hydrogen, fluorineor chlorine, R³ is hydrogen, C₁-C₄-alkyl, NO₂, COOR⁵ or OR⁶, where R⁵and R⁶ independently of one another are hydrogen, C₁-C₄-alkyl,C₃-C₄-alkenyl, C₃-C₄-alkynyl, C₁-C₄-alkoxy-C₁-C₄-alkyl orC₁-C₄-alkoxycarbonyl-C₁-C₄-alkyl.
 6. A process as claimed in claim 1,wherein R¹ is methyl.
 7. A process as claimed in claim 1, wherein L isselected from the group consisting of iodine, bromine, chlorine and agroup OSO₂—OR¹ or [O(R¹)₂]r.
 8. A process as claimed in claim 6, whereinthe compound R¹-L is dimethyl sulfate.
 9. A process as claimed in claim1, wherein the reaction of compound III or IV with the alkylating agentR¹-L is carried out in the presence of a base.
 10. A process as claimedin claim 1, wherein the alkylating agent R¹-L is employed in an amountof from 1 to 2 mol per mole of the compound III or IV.
 11. A process asclaimed in claim 1, wherein difluoromethane is used in an amount of from3 to 10 mol per mole of compound III or IV.